Abstract ? Washington University's PrecISE Clinical Center The overall impact of severe asthma on individuals affected by this disease as well as society is substantial. Treatment for severe asthma is now focusing on tailoring treatment to particular phenotypes driven by the endotypes yet the evidence for this approach is lacking. Key phenotypes which have supporting evidence for appropriate biomarkers and therapy based on their endotype include eosinophilic-, T2- and mucin-driven disease states. This proposal contains a precision-medicine, biomarker-driven, highly novel adaptive controlled trial to establish a new treatment paradigm for severe asthma as proposed by the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network RFA. In the current proposal, our overall hypothesis is that a specific phenotype (eosinophilic, T2 or mucin) will respond better to a biologic therapy targeted specifically to that phenotype than an empirical approach. Specifically, we hypothesize that patients with the following phenotypes will differ in treatment responses: i) eosinophilic - treatment with anti-IL5 or anti-IL4R? monoclonal antibody (mAb) is superior to anti-IgE, ii) T2 - treatment with anti-IL4R? or ?IL5 is superior to anti-IgE and iii) mucus - treatment with either anti-IL4R? or - IL5 is superior to anti-IgE. In this adaptive trial design, we will use two short-term response indicators, improvement in FEV1 of 100 ml or greater from baseline and/or improvement in asthma control (ACQ) score of 0.5 or greater, to determine if the patient is responding or not. The primary endpoint will be the asthma exacerbation rate. Accordingly, our specific aims are to study adolescent and adult patients with severe persistent exacerbation-prone asthma to: Aim I. Evaluate which biologic therapy, anti-IL4R?, anti-IL5 or anti-IgE mAb, is most effective among patients with eosinophilic asthma (blood eosinophil ?300 cells/L) who demonstrate a short term- response and which demonstrates an acceptable safety profile. Aim II. Evaluate which biologic therapy, anti-IL4R?, anti-IL5 or anti-IgE mAb, is most effective among patients with T2 asthma (high T2 sputum signature) who demonstrate a short term-response and which demonstrates an acceptable safety profile. Aim III. Evaluate which biologic therapy, anti-IL4R?, anti-IL5 or anti-IgE mAb, is most effective among patients with mucus-driven asthma (high mucus score on qCT chest) who demonstrate a short term- response and which demonstrates an acceptable safety profile. Aim IV. a. Determine whether airway remodeling (change in qCT wall area) is modified by biologic therapy. Aim IV. b. Evaluate the ability of a positive short-term response within each biologic therapy to predict exacerbations and airway remodeling.